Disposition of voriconazole during continuous veno-venous haemodiafiltration (CVVHDF) in a single patient

OBJECTIVES: To determine whether voriconazole dosage adjustment is required during continuous veno-venous haemodiafiltration (CVVHDF). METHODS: Voriconazole pharmacokinetics were studied in a critically ill patient under CVVHDF. The analysis was carried out for 12 h following a 6 mg/kg dose. Voriconazole concentrations were measured by HPLC in blood inlet and outlet lines and in dialysate. RESULTS: The total body clearance of voriconazole was 20.3 L/h, with a terminal half-life of 13.7 h and a distribution volume of 399 L. The estimated sieving coefficient was 0.53 and the filtration-dialysis clearance 1.2 L/h. CONCLUSIONS: CVVHDF does not significantly affect voriconazole disposition and requires no dosage adjustment.     

Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration

OBJECTIVE: Moxifloxacin is an 8-methoxy quinolone with a broad range of activity against clinically important pathogens. Therefore it is frequently administered in severe respiratory tract infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporeal renal replacement therapy for intensive care patients suffering from sepsis and multiple organ failure. The aim of this study was to investigate the pharmacokinetics of intravenous moxifloxacin in anuric critically ill patients undergoing CVVHDF. PATIENTS AND METHODS: Pharmacokinetic analysis was performed in nine intensive care patients with acute renal failure and suspected or proven infection sensitive to moxifloxacin, who received moxifloxacin 400 mg intravenously once daily. The concentration of moxifloxacin in serum and ultradiafiltrate was determined by HPLC. RESULTS: Peak and trough serum concentrations were 3.76 +/- 2.02 mg/L and 0.24 +/- 0.14 mg/L, respectively, at the arterial port after the first dose. The mean elimination half-life was 9.87 +/- 3.26 h, the volume of distribution 270 +/- 133 L and the calculated AUC0-24 18.41 +/- 8.46 mg.h/L. Total clearance was 19.09 +/- 8.22 L/h and the clearance of haemodiafiltration 1.63 +/- 0.33 L/h. CONCLUSIONS: The pharmacokinetics of moxifloxacin in critically ill patients with acute renal failure undergoing CVVHDF was comparable to healthy subjects and patients without renal impairment. We recommend 400 mg of intravenous moxifloxacin once per day in anuric patients during CVVHDF.     

Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.     

Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure

Meropenem elimination was studied in six patients with acute renal failure on continuous venovenous haemofiltration (CVVH) or continuous veno-venous haemodiafiltration (CVVHDF) 1 L/h and 2 L/h for 12 h. Meropenem 1 g was given iv over three dialysis periods, and plasma, ultrafiltrate/dialysate and urine concentrations of meropenem were determined. The half-life of meropenem was significantly longer (P < 0.05) during CVVH (7.5 +/- 2.0 h; mean +/- S.D.) than during CVVHDF 1 L/h (5.6 +/- 1.4 h) or 2 L/h (4.8 +/- 1.2 h). Meropenem clearance was 3.27 +/- 2.30 L/h, 4.72 +/- 2.69 L/h and 5.71 +/- 3.58 L/h in CVVH, CVVHDF 1 L/h and CVVHDF 2 L/h, respectively (P < 0.05 between CVVH and CVVHDF). Patients with renal failure on CVVHDF 1 or 2 L/h should be treated with meropenem 1 g bid; 500 mg tid may be enough for patients on CVVH.     

Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure.

The elimination of the piperacillin/tazobactam combination was studied in six patients with acute renal failure undergoing either continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 h. Piperacillin 4 g/tazobactam 0.5 g was given iv on three successive treatment periods and their concentrations in plasma, ultrafiltrate/dialysate and urine were determined for 12 h after each dose. The elimination half-life of piperacillin during CVVH (7.7 +/- 2.3 h; mean +/- s.d.) was significantly longer than during CVVHDF 1 L/h (6.7 +/- 1.9 h) or 2 L/h (6.1 +/- 2.0 h) (P< 0.05). Corresponding values for tazobactam were 13.9 +/- 3.9, 11.6 +/- 3.3 and 9.4 +/- 2.4 h, respectively (P< 0.05). Total piperacillin clearance during CVVH (3.89 +/- 1.23 L/h) was significantly lower than during CVVHDF 1 L/h (5.06 +/- 1.68 L/h) or 2 L/h (5.48 +/- 2.11 L/h) (P< 0.05). The corresponding tazobactam clearance values were 2.42 +/- 0.75, 3.13 +/- 0.66 and 3.75 +/- 1.43 L/h, respectively. The mean 12 h elimination of piperacillin and tazobactam in ultrafiltrate/dialysate was 29% and 37% during CVVH, 42% and 57% during CVVHDF (1 L/h), and 46% and 69% during CVVHDF (2 L/h). We recommend 8 hourly dosing of patients with renal failure on CVVH or CVVHDF with dialysis flow rates of 1 or 2 L/h treated with piperacillin 4 g/tazobactam 0.5 g.     

Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia

Introduction

In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting.

Method

Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m² AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography.

Results

The mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively.

Conclusion

We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.     

Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods

Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Delta/cdr1Delta, cdr2Delta/cdr2Delta, flu1Delta/flu1Delta, and mdr1Delta/mdr1Delta) and calcineurin subunit A (cnaDelta/cnaDelta) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% +/- 5.0%/96.5% +/- 2.4% (HPLC) and 94.9% +/- 6.1%/94.7% +/- 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% +/- 1.5%/5.4% +/- 0.9% and 6.5% +/- 2.5%/4.0% +/- 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg x h/liter (range, 12.9 to 71.1) on the first and 27.4 mg x h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg x h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg x h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.     

Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites.

The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < or = 15 mg/L while group III included three patients with serum creatinine > 15 mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the ascitic fluid (AF) of 6.2 +/- 2.3 mg/L at 4 h, and of 8.7 +/- 4.4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC90 for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0.001) from 1.82 +/- 0.14 h in group I to 6.6 +/- 2.1 h and to 8.87 +/- 0.2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0.001) of the total body clearance (Cl) of aztreonam from 84 +/- 8 mL/h/kg in group I to 209 +/- 87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122 +/- 50 mL/h/kg. The AUC0-infinity serum was 137.5 +/- 12.2, 78.5 +/- 24.9 and 151 +/- 42 mg.h/L in groups I, II and II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic disposition of isoxicam in hepatic cirrhosis

To determine the effect of liver dysfunction on the absorption and disposition of isoxicam, we administered a single oral dose of 200 mg to 8 patients with alcoholic cirrhosis, and followed the plasma concentration-time curve for 96 h. The calculated isoxicam disappearance t 1/2 of 30 +/- 19.1 h in these patients was not different from the mean value of 31 +/- 5.7 h obtained in 10 normal subjects studied earlier by our group; however, interindividual variation was larger. No differences in lag time (0.42 +/- 0.3 vs 0.49 +/- .2 h) or time to peak concentration (9.0 +/- 2.5 vs 10.0 +/- 2.9 h) were observed. However, the peak plasma isoxicam concentrations and the areas under the plasma concentration-time curves (AUC) were reduced 32% (p less than 0.01) and 41% (p less than 0.01), respectively. Plasma protein binding of isoxicam studied by equilibrium dialysis was 80 +/- 16% in the cirrhotic patients compared with 96 +/- 1.4% in the normal volunteers (p less than 0.02), again with larger interindividual variation noted in patients with cirrhosis. The binding did not correlate significantly with any laboratory tests of liver function or with the AUC for plasma isoxicam. As compared to the normal subjects, these cirrhotic patients had decreased plasma isoxicam binding, peak plasma isoxicam concentrations and AUC, without a significant change in the apparent disappearance half-life of total plasma isoxicam after a single oral dose.     

Effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of s-(+)- and R-(-)-Ibuprofen

Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(-)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(-)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C(max)) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t(1/2)) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C(max) was 116% of the control value (P < 0.05). The mean t(1/2) of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(-)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.     

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.     

Pharmacokinetics of ciprofloxacin in ICU patients on continuous veno-venous haemodiafiltration

OBJECTIVES: To investigate the pharmacokinetics of intravenous ciprofloxacin 200 mg every 8 h in critically ill patients on continuous veno-venous haemodiafiltration (CVVHDF), one form of continuous renal replacement therapy (CRRT). DESIGN AND SETTING: Open, prospective clinical study in a multidisciplinary, intensive care unit in a university-affiliated tertiary referral hospital. PATIENTS: Six critically ill patients with acute renal failure on CVVHDF. INTERVENTIONS: Timed blood and ultrafiltrate samples were collected to allow pharmacokinetics and clearances to be calculated of initial and subsequent doses of 200 mg intravenous ciprofloxacin. CVVHD was performed with 1 l/h of dialysate and 2 l/h of predilution filtration solution, producing 3 l/h of dialysis effluent. The blood was pumped at 200 ml/min using a Gambro BMM-10 blood pump through a Hospal AN69HF haemofilter. MEASUREMENTS AND RESULTS: Ten pharmacokinetic profiles were measured. The CVVHDF displayed a urea clearance of 42 +/- 3 ml/min, and removed ciprofloxacin with a clearance of 37 +/- 7 ml/min. This rate was 2-2.5 greater than previously published for ciprofloxacin in other forms of CRRT. On average the CVVHDF was responsible for clearing a fifth of all ciprofloxacin eliminated (21 +/- 10%). The total body clearance of ciprofloxacin was 12.2 +/- 4.3 l/h. The trough concentration following the initial dose was 0.7 +/- 0.3 mg/l. The area under the plasma concentration time curves over a 24-h period ranged from 21 to 55 mg.h l-1. CONCLUSIONS: Intravenous ciprofloxacin 600 mg/day in critically ill patients using this form of CRRT produced adequate plasma levels for many resistant microbes found in intensive care units.     

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.     

Pharmacokinetics and pharmacodynamics of once-daily arbekacin during continuous venovenous hemodiafiltration in critically ill patients

This study examined the pharmacokinetics of arbekacin during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamics to consider arbekacin dosage adaptation in CVVHDF. Arbekacin was administered by 0.5-h infusion once daily, using a polymethyl methacrylate membrane hemofilter, to three critically ill patients undergoing CVVHDF; the flow rates were 0.8 l/h for the filtrate and 0.6 l/h for the dialysate. The drug concentrations in plasma and in the filtrate-dialysate were determined using a fluorescence polarization immunoassay and analyzed pharmacokinetically. The average sieving coefficient of arbekacin was 0.739 and the average drug clearance by CVVHDF was 1.03 l/h. A pharmacokinetic model with three compartments (1, central; 2, peripheral; 3, filtrate-dialysate side hemofilter) accurately reflected the concentration-time data for both plasma and filtrate-dialysate. The pharmacokinetic model assessed the pharmacodynamic profile of arbekacin once-daily regimens (0.5-h infusions) at filtrate-dialysate flow rates of 1.4 and 2.8 l/h, and demonstrated that only the 150-mg and 200-mg regimens achieved an effective target range for C_max (9–20 μg/ml), suggesting that empirical dosages lower than the usual 150–200 mg should be avoided in patients undergoing CVVHDF. The minimum regimens needed to achieve an effective pharmacodynamic target for the free C_max/MIC ratio (>8) were 75 mg for an MIC of 0.5 μg/ml, 200 mg for an MIC of 2 μg/ml, and 400 mg for an MIC of 4 μg/ml. These results will help us to better understand the pharmacokinetics of arbekacin during CVVHDF, while also helping in the selection of the appropriate arbekacin regimens, based on a pharmacodynamic assessment, for patients receiving this renal replacement therapy.     

Continuous infusion versus intermittent administration of meropenem in critically ill patients.

This prospective crossover study compared the pharmacokinetics of meropenem by continuous infusion and by intermittent administration in critically ill patients. Fifteen patients were randomized to receive meropenem either as a 2 g iv loading dose, followed by a 3 g continuous infusion (CI) over 24 h, or by intermittent administration (IA) of 2 g iv every 8 h (q8h). Each regimen was followed for a period of 2 days, succeeded by crossover to the alternative regimen for the same period. Pharmacokinetic parameters (mean +/- SD) of CI included the following: concentration at steady state (Css) was 11.9+/-5.0 mg/L; area under the curve (AUC) was 117.5+/-12.9 mg/L x h. The maximum and minimum serum concentrations of meropenem (Cmax, Cmin) and total meropenem clearance (CItot) for IA were 110.1+/-6.9 mg/L, 8.5+/-1.0 mg/L and 9.4+/-1.2 L/h, respectively. The AUC during the IA regimen was larger than the AUC during CI (P < 0.001). In both treatment groups, meropenem serum concentrations remained above the MICs for the most common bacterial pathogens. We conclude that CI of meropenem is equivalent to the IA regimen and is therefore suitable for treating critically ill patients. Further studies are necessary to compare the clinical effects of CI and IA in this patient group.     

Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients

The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.     

Influence of continuous venovenous hemofiltration and continuous venovenous hemodiafiltration on the disposition of doripenem

The pharmacokinetics, safety, and tolerability of a single 1-hour, 500-mg intravenous infusion of doripenem were assessed in dialysis-dependent subjects with stage 5 chronic kidney disease undergoing continuous renal replacement therapy (CRRT) via 12-hour continuous venovenous hemofiltration (CVVH) (n = 6) or continuous venovenous hemodiafiltration (CVVHDF) (n = 5). Healthy volunteers were also assessed (n = 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysis-dependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3- and 5-fold greater, respectively, than those in healthy subjects: for doripenem, 98 μg·h/ml for CVVH and 77 μg·h/ml for CVVHDF versus 32 μg·h/ml for healthy subjects, and for doripenem-M-1, 24 μg·h/ml for CVVH and 22 μg·h/ml for CVVHDF versus 4.7 μg·h/ml for healthy subjects. The mean sieving coefficients and saturation coefficients were >0.67 for both doripenem and doripenem-M-1. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38% and 29%, and clearances of doripenem were 22 and 25 ml/min. Both CVVH and CVVHDF efficiently removed doripenem and doripenem-M-1. Despite significant removal of drug by CVVH and CVVHDF, a single 1-hour, 500-mg doripenem infusion produced significantly higher plasma concentrations of doripenem, higher systemic exposure (area under the plasma concentration-time curve from time zero to 12 h after the start of infusion [AUC(0-12)]), and longer half-life (t(1/2)) in subjects receiving CVVH or CVVHDF than in healthy volunteers. The recovery of drug in ultrafiltrate and ultrafiltrate/dialysate and the enhanced rate of reduction of plasma concentrations indicate that CVVH and CVVHDF significantly augmented residual total body clearance of doripenem in subjects receiving CRRT. Doripenem dosage regimens for patients receiving CRRT thus need to be adjusted.     

Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients.

Published recommendations for the optimal dosing regimen of ceftazidime in critically ill patients with continuous venovenous haemofiltration (CVVH) differ. The aim of this prospective study was to analyse the pharmacokinetic and pharmacodynamic parameters of ceftazidime during CVVH with a high-flux polysulphone membrane, and derive a dosage recommendation. Twelve critically ill patients (five female, seven male) with acute renal failure undergoing CVVH using a 0.7 m(2) polysulphone high-flux membrane were investigated. All patients received ceftazidime 2 g i.v. q8h. Peak ceftazidime concentrations were 58.2 +/- 11.6 mg/L, with trough concentrations 14.0 +/- 3.2 mg/L at the arterial port. The elimination half-life, haemofiltration clearance, volume of distribution and total removal were 4.3 +/- 0.6 h, 32.1 +/- 7.9 mL/min, 36.4 +/- 6.4 L and 74.5 +/- 6.5%, respectively. Based on these pharmacokinetic parameters and that maximal killing is at 4 x MIC we recommend at least ceftazidime 2 g i.v. q8h.     

In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model

In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (R(2) for AUC/MIC ratio = 82%, R(2) for peak level/MIC ratio = 63%, R(2) for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean +/- standard deviation, 24 +/- 17 [P = 0.45]). These AUC/MIC ratios observed for free drug are similar to those observed for other triazoles in this model.     

Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia

OBJECTIVE: To determine the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Sixteen critically ill adult patients with ventilator-associated pneumonia. INTERVENTIONS: All subjects received 1-hr intravenous infusions of linezolid 600 mg twice daily. After 2 days of therapy, the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean +/- sd linezolid peak and trough concentrations were 17.7 +/- 4.0 mg/L and 2.4 +/- 1.2 mg/L in plasma and 14.4 +/- 5.6 mg/L and 2.6 +/- 1.7 mg/L in epithelial lining fluid, respectively, showing a mean linezolid percentage penetration in epithelial lining fluid of approximately 100%. The mean +/- sd area under concentration-time curve during the observational period (AUC0-12) was 77.3 +/- 23.7 mg x hr/L, corresponding to a mean AUC0-24 of 154.6 mg x hr/L. CONCLUSIONS: Our study shows satisfactory results, with linezolid concentrations exceeding the susceptibility breakpoint for Gram-positive bacteria in both plasma and epithelial lining fluid. This suggests that a dosage of 600 mg administered intravenously twice daily to critically ill patients with Gram-positive ventilator-associated pneumonia would achieve success against organisms with minimum inhibitory concentrations as high as 2-4 mg/L in both plasma and epithelial lining fluid.